L-Carnitine, a type of betaine, which is also known as vitamin BT, is an important compound involved in in vivo fatty acid metabolism. L-Carnitine has also attracted attention as a therapeutic for cardiac diseases (Japanese Unexamined Patent Publication No. S54-76830), as a therapeutic for hyperlipemia (Japanese Unexamined Patent Publication No. S54-113409) and as a therapeutic for venous diseases (Japanese Unexamined Patent Publication No. S58-88312).
As processes for preparing carnitine, a type of betaine, a number of processes have been reported. For example, Japanese Unexamined Patent Publication No. S57-165352 discloses a process in which L-carnitine is obtained from D-mannitol as the starting material; Japanese Unexamined Patent Publication No. S62-272983 discloses a process in which (R)-3,4-epoxybutyric acid ester is isolated selectively from (R,S)-3,4-epoxybutyric acid ester with an asymmetric hydrolase and then treated with trimethylamine or trimethylamine hydrochloride to thereby produce L-carnitine; Japanese Unexamined Patent Publication No. 2002-544252 discloses a process in which (S)-(−)-chlorosuccinic acid derivative is converted to a corresponding acid anhydride, which is then treated with trimethylamine to thereby produce L-carnitine; and Japanese Unexamined Patent Publication No. 2002-529528 discloses a process in which alkyl-4-chloro-3-oxobutylate is subjected to selective, asymmetric hydrogen reduction using a ruthenium complex catalyst to thereby produce alkyl-(R)-(+)-4-chloro-3-hydroxybutylate, which is then subjected to quaternary amination with trimethylamine to thereby obtain L-carnitine.
As seen from the disclosure in the above-listed patent documents, a step of introducing a quaternary amino group into the C4 skeleton using trimethylamine is an important step unavoidable in carnitine preparation. Besides, in many occasions, the yield at this step affects the total yield greatly. With respect to this quaternary amination, Japanese Unexamined Patent Publication No. H2-142758 discloses a process in which methyl 4-halogeno-3-hydroxybutyrate is quaternary aminated with trimethylamine in the presence of ketone solvent, and then the resultant butyric acid ester derivative is hydrolyzed. This quaternary amination is carried out in an autoclave at temperatures as high as 80° C. using alcohol as a solvent and anhydrous trimethylamine. Since olefin is produced as dehydration of methyl 4-halogeno-3-hydroxybutyrate proceeds, the selection ratio is remarkably low (about 30-40%) and the reaction time is rather long (20 hr or more). It is described that use of ketone solvent improves selectivity However, though the selectivity is greatly improved, the reaction time is still prolonged. Even 50 hr after the start of the reaction, the conversion ratio of methyl 4-halogeno-3-hydroxybutyrate is only about 80%. When ether or toluene is used as a solvent, the reaction time is further prolonged and the selection ratio does not rise considerably.
Japanese Patent Unexamined Publication No. H2-27995 discloses a process in which 30% aqueous solution of trimethylamine is added to γ-chloro-β-hydroxybutyronitrile and the resultant mixture is subjected to quaternary amination. The solid obtained by leaving the reaction solution at 4° C. overnight and then vacuum filtering has a yield of only about 75% even as carnitine nitrile chloride of 100% purity, which can not be said a high yield. Japanese Patent Unexamined Publication No. S60-258487 discloses a process in which largely excessive anhydrous trimethylamine is added to 4-chloro-3-hydroxybutyronitrile, and the resultant mixture is reacted without solvent in a 100° C. autoclave to thereby obtain carnitine nitrile chloride at a yield of 94%. The reaction conditions thereof are severe and the reaction time is rather long (24 hr).
On the other hand, as an example of reaction introducing an amino group not through quaternary amination, Japanese Examined Patent Publication No. 53-13611 discloses a process in which γ-chloro-β-hydroxybutylic acid amide is reacted with largely excessive (about 100 equivalents) ammonia at about 20° C. for 16 hr to thereby obtain γ-amino-β-hydroxybutylic acid amide. This process has two problems, i.e., use of largely excessive ammonia and the length of reaction time. A similar reaction is disclosed in Heterocycles, Vol. 53, No. 1, 2000. In this reaction, largely excessive (about 100 equivalents) aqueous ammonia is added to (S)-4-chloro-3-hydroxybutanamide and the resultant mixture is reacted in a tightly sealed system at 120° C. for 8 hr to thereby introduce an amino group. This reaction also has the problems of use of largely excessive ammonia and the length of reaction time.
As described above, it has been known that reacting 4-halogeno-3-hydroxybutyramide with largely excessive ammonia for a long time results in the introduction of an amino group. However, nothing has been known as to reacting with trialkylamine.
With respect to the step of quaternary amination with trialkylamine which greatly affects the total yield in betaine (such as carnitine) preparation processes, conventional quaternary amination of methyl 4-halogeno-3-hydroxybutylic acid or γ-chloro-β-hydroxybutyronitrile with trimethylamine is accompanied with progress of side reactions. Thus, it has been difficult to obtain a quaternary aminated product of interest at a high yield.